Corticosteroid and Antifungal Alternative Treatments for Seborrheic Dermatitis: a Review

Home , Climbazole, Pimecrolimus, Zinc pyrithione

FABAD J. Pharm. Sci., 45, 1, 77-89, 2020

Review Articles Corticosteroid and Antifungal Alternative Treatments for Seborrheic Dermatitis: A Review

Anita Maria DJUNAIDI*°

Corticosteroid and Antifungal Alternative Treatments for Seboreik Dermatit Için Kortikosteroid ve Antifungal Alternatif Seborrheic Dermatitis: A Review Tedaviler: Bir Derleme

SUMMARY ÖZ

Alternative therapy is increasingly utilized as adjuncts to most Seboreik dermatit (SD) için geleneksel tedavilerle (topikal commonly used conventional treatments (such as topical antifungal antifungal ve kortikosteroid gibi) ilaveten alternatif tedavilerin kullanımı çoğaltmaya başlamıştır. Topikal antifungal ilaçlar and corticosteroid) of seborrheic dermatitis (SD). Topical antifungal değişen başarı oranlarıyla yaygın olarak kullanılmaktadır ve topikal medications have been used with varying success, and long-term kortikosteroidlerin uzun süreli kullanımının çeşitli yan etkileri olduğu use of topical corticosteroid is widely known to cause various side iyi bilinmektedir. Bu makalede, mevcut alternatif tedaviler ve yan effects. This article reviews trial studies of SD therapies other than etkileri hakkında bilgi vermek amacıyla, kortikosteroid ve antifungal corticosteroid and antifungal, aiming to offer information regarding dışı SD tedavilerine ait klinik çalışmalar derlenmektedir. Çalışma existing alternative therapies and their side effects. Searches PRISMA kılavuzlarına dayanarak Pubmed ve Cochrane veri were performed on PubMed and Cochrane database focusing on tabanlarından araştırılan klinik calışmalara odaklanmaktadır. Veri clinical trials according to the PRISMA guidelines. A total 317 tabanı araştırmalarından bulunan toplam 317 çalışma içerisinden studies were identified from database searching. After duplicate duplikasyonların çıkarılması ve uygunluk taraması yapıldıktan sonra 40 çalışma nihai analize dahil edilmiştir. Bu çalışmada incelenen removal and eligibility screening, 40 studies were included in alternatif tedavi yaklaşımları: bitkisel içerikler (el kremleri ve bitkisel the final analysis. Alternative modalities reviewed in this study şampuanlar, Myrtus communis L., Quassia amara, çay ağacı yağı, include: herbal ingredients (herbal shampoo and handcream, Vitreoscilla filiformis), kalsinörin inhibitörleri, bal, izotretinoin, Myrtus communis L., Quassia amara, tea tree oil, Vitreoscilla lipohidroksi asit, lityum, metronidazol, fototerapi, nikotinamid, filiformis), calcineurin inhibitor, honey, isotretinoin, lipohydroxy oral homeopatik çözelti, üre-laktik asit-propilen glikol (K301) acid, lithium, metronidazole, phototherapy, nicotinamide, oral çözeltisi ve çinko piritiyon. Bitkisel içerikler için aktif maddelere ait homeopathic solution, solution of urea-lactic acid-propylene glycol herhangi bir standardizasyon, saflık tayini ya da konsatrasyona ait (K301), and zinc pyrithione. For herbal ingredients, there is still no açık bilgiler bulunmamaktadır. Bitkisel olmayan tedaviler arasında standardisation of active ingredients, purity, or concentrations. The pozitif klinik iyileşme ile sonuçlanan kalsinörin inhibitörleri en çok çalışılanlardır (pimekrolimus için 12 çalışma, takrolimus için 5 most highly studied non-herbal alternative therapy was calcineurin çalışma bulunmaktadır). Hafif yanma hissi, kızarıklık ve kaşıntılar inhibitors (pimecrolimus with twelve studies and tacrolimus with en çok görülen yan etkilerdendir. Tedavilerin çoğunluğu olumlu ve five studies) that yielded positive clinical improvements. The most güvenli sonuçlar gösterdiği halde, bu tedavilerin uzun süreli kullanım common side effects observed were mild burning sensations, erythema, için hastalara tavsiye edilmeden önce daha fazla araştırma yapılması and pruritus. While most therapies appear to be beneficial and safe, gerekmektedir. further research is necessary before these therapies can be consistently recommended to patients, especially for long-term use.

Key Words: Seborrheic dermatitis, alternative treatment, Anahtar kelimeler: Seboreik dermatit, alternatif tedavi, antifungal, corticosteroid, herbal, calcineurin inhibitor antifungal, kortikosteroid, bitkisel, kalsinörin inhibitörleri

Received: 27.07.2019 Revised: 18.11.2019 Accepted: 25.12.2019

* ORCID: 0000-0002-6232-6714 , Brawijaya Tingkat III General Hospital, Surabaya, Indonesia

º Corresponding Author: Anita Maria Djunaidi Brawijaya Tingkat III General Hospital, Kesatriyan 17, Surabaya 60242, Indonesia, Phone/Fax : +6231 5682088 / +6231 5611272, Email: [email protected] 77 Djunaidi

INTRODUCTION medications in conjunction with topical corticosteroids are often used. Topical antifungal medications Seborrheic Dermatitis (SD) is a chronic papu- have been used with varying success, and oral anti- losquamous disorder that affects infants and adults. fungals should only be reserved for severe, refracto- It characteristically manifests in parts of the body ry cases due to potential drug interactions and side with high concentrations of sebaceous follicles and effects (Collins & Hivnor, 2012). Long term use of active sebaceous glands, such as the face, scalp, ears, topical corticosteroid is also widely known to cause upper trunk, and flexures (inguinal, inframammary, various dermatologic side effects (Coondoo, Phiske, and axillary) (Collins & Hivnor, 2012). SD often pres- Verma, & Lahiri, 2014). Therefore, this study reviews ents as well-demarcated erythematous plaques with SD treatments other than antifungal medications and greasy-looking, yellowish scales of varying extent corticosteroid, to help physicians remain informed on (Borda, Perper, & Keri, 2019). Its pathogenesis is still evidence-based recommendations for various alterna- not fully understood, some postulate that the disorder tive SD therapies and hence better patient counseling results from colonization of species from the genus could be performed. The articles used are trial studies Malassezia (formerly, Pityrosporum) on the skin (Berk published from January 1st, 2000 onwards, with the & Scheinfeld, 2010). Although non-life threatening, intention of offering fresh, up-to-date information. SD can have a great impact on someone’s quality of life, leading to low self-esteem and a negative social METHODS/LITERATURE RESEARCH image especially among young female group and peo- A review of medical literatures was conducted ple who suffer from scalp lesions (Araya, Kulthanan, according to the recommendations of PRISMA (Pre- & Jiamton, 2015). ferred Reporting Items for Systematic Reviews and Seborrheic dermatitis is a common occurrence Meta-Analyses) guidelines. The keywords (“seborrhe- worldwide. Its incidence mostly occurs during three ic dermatitis” OR “seborrhea”) AND (“alternative” OR age periods – the first three months of life, puberty, “treatment” OR “shampoo”) were used to search trial and adulthood with the peak of 40-60 years of age (del studies from PubMed and Cochrane database. After Rosso, 2011). In adults, the SD incidence is around removal of duplicates, eligible studies were screened 1-3%, with men affected more frequently than women by title and abstract. Studies were included if they de- (3.0% vs. 2.6%) in all age groups. This suggests that scribed any clinical effects on SD following alternative sex hormones such as androgens may play a role in therapies. Studies were excluded if they were irrele- the development of SD. Various ethnic groups do not vant, there were no abstract available, the studies were show any apparent difference in SD incidence (Sam- published prior to January 1st, 2000, and they were paio et al., 2011). conducted in in-vitro experiments. Irrelevant studies were the trials that did not include SD therapy oth- Seborrheic dermatitis is a chronic condition er than antifungal medications and or corticosteroid. which at some cases may require a long-term treat- The remaining studies were then read in full text to ment, therefore it is imperative to choose a treatment confirm eligibility. Studies that do not have full-texts modality with maximum benefits and most tolerable electronically available and studies that were not in side effects. The treatment of SD involves eradicating English or do not have English translations were also fungus as well as reducing the inflammatory process excluded. Study selection and studies on alternative and sebum production (Berk & Scheinfeld, 2010). treatments for seborrheic dermatitis are shown in Fig- With those mechanisms in mind, topical antifungal ure 1 and Table 1 respectively.

FABAD J. Pharm. Sci., 45, 1, 77-89, 2020

Trial studies identified from database n = 317 PubMed n = 172 Cochrane n = 145

Duplicates n = 92

Studies screened by title/abstract n = 225

Excluded n = 172 . Irrelevant studies = 127 . No abstract available = 6 . Publication date prior to January 1st, 2000 = 37 . In vitro study = 2

Full-text studies screened for eligibility n = 53

Excluded n = 13 . No full-text article available = 6 . Full-text languages other than English = 7

Studies included in the review n = 40

Figure 1. Seborrheic dermatitis: study selection for alternative treatment

RESULTS Table 1. Studies on alternative treatments for seborrheic dermatitis

Alternative treatment; Ref- Number Treatment method /Dura- Results Adverse Effects erence of tion (weeks) patients Herbal and Zinc Pyrithione 50 Shampoo at least twice A reduction in erythema No adverse side effects were Shampoo and Scalp Lotion. weekly and the scalp lotion and flaking. noted. (Barak-Shinar & Green, 2018) was used daily before bed- time for 42 days. Honey. 30 Honey was applied every A reduction in itching, No adverse side effects were (Al-Waili, 2001) other day for 4 weeks. scaling, and skin lesions. noted. Improved patients were Subjective improvement in then divided into 2 groups, hair loss. Prophylactic group treatment was applied once experienced no relapse weekly for 6 months. compared to control group. . Prophylactic group: honey. . Control group: vehicle. Isotretioin 10mg oral. 45 Treatment for 6 months. In group ISO, a reduction in Group ISO: Cheilitis, abnor- (de Souza Leão Kamamoto, . Group ISO: 10mg rate of sebum production. mal serum lipids, body and Sanudo, Hassun, & Bagatin, isotretinoin every other Patient opinion, investiga- facial skin fragility, head- 2017) day. tor, and quality of life as- ache, eczema, eye problems, . Group X: topical treat- sessments improved in both nosebleeds. ment (antiseborrheic groups. Less frequent: muscle ache, shampoo three times herpes simplex, tiredness, weekly, salicylic acid joint ache, pruritus, mood soap twice daily). change, abnormal liver function.

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Isotretinoin oral in very low 11 Treatment for 6 months. A reduction in sebum Facial redness, dryness of dose. . Group I: 5mg daily. production and sebaceous eyes and conjunctivitis, (Geißler, Michelsen, & . Group II: 2.5 mg daily. gland size in all groups. A cheilitis, dry vestibulitis in Plewig, 2003) . Group III: 2.5 mg three reduction of lipids in group group I and II. times weekly. I and II. Lipohydroxy acid containing 100 Every other day for 4 weeks. The tolerance, the global No adverse side effects were shampoo. . Group I: 0.1% lipohy- efficacy, and cosmetic ac- noted. (Seite, Rougier, & Talarico, droxy acid (LHA) and ceptability of group I were 2009) 1.3% salicylic acid. significantly better. . Group II: 5% ci- clopiroxolamine (CPO), 3% salicylic acid, and 0.5% menthol. Lithium gluconate. 129 Twice daily for 8 weeks. Clinical remission is better Mild erythema and burning. (Dreno & Moyse, 2002) . Group I: 8% lithium in group I. gluconate. . Group II: placebo Lithium gluconate. 557 Twice daily for 8 weeks. In ITT and PP group, sat- Erythema, burning, dryness, (Dreno, Chosidow, Revuz, . Intent to treat protocol isfaction rate was higher in and upper respiratory tract Moyse, & STUDY INVESTI- (ITT): 288 patients. those with lithium treat- infections. Lithium gluco- GATOR GROUP, 2003) . Patients protocol (PP): ment. nate was found to be sticky. 269 patients.

Metronidazole 0.75% gel. 67 Treatment gel or placebo for Metronidazole is only as No adverse side effects were (Ozcan, Seyhan, & Yologlu, 4 weeks and were addition- effective as placebo. The noted. 2007) ally followed up for another disease severity quickly re- 4 weeks. turns to the basal levels after treatment cessation. Metronidazole 0.75% gel. 84 Twice daily for 8 weeks. No statistically significant No adverse side effects were (Koca, Altinyazar, & Eştürk, . Group I: 0.75% metro- difference was found be- noted. 2003) nidazole. tween the treatment groups. . Group II: placebo. Metronidazole 1% gel. 156 Twice daily for 4 weeks. Higher level of satisfaction No adverse side effects were (Mohamad Goldust, Rezaee, . Group I: 2% sertacon- was observed in group I. noted. & Raghifar, 2013) azole. . Group II: 1% metronidazole. Metronidazole 1% gel. 56 Twice daily for 8 weeks. In group I, a reduction in Redness and pruritus. (Siadat, Iraji, Shahmoradi, . Group I: 1% metroni- mean SD severity score. Enshaieh, & Taheri, 2006) dazole. . Group II: placebo. Myrtus communis L. 90 Once every 3- 4 days for In both groups, significant No adverse side effects were (Chaijan, Handjani, Zarshe- 30 days. improvement in all outcome noted nas, Rahimabadi, & Tavakko- . Group I: anti-dandruff measures (Excoriation li, 2018) (Myrtus communis L.) Pruritus Grading, Adherent shampoo. Scalp Flaking Score, Red- . Group II: anti-dandruff ness of Scalp Skin, Grading (ketoconazole 2%) of Scalp Skin Involvement). shampoo. Narrow-band ultraviolet B 18 Three times weekly until All patients responded well Occasional moderate ery- (TL-01) phototherapy. absence of symptoms or to a to treatment. Complete thema. (Pirkhammer, Seeber, Hönigs- maximum of 8 weeks. clearance in 6 patients, mann, & Tanew, 2000) significant improvement in 12 patients. Nicotinamide 4% cream. 48 Once daily for 12 weeks. Reduction of 75% of the Minimal burning sensation (Fabbrocini, Cantelli, & Mon- . Group I: 4% nicotin- total score of erythema, and pruritus. frecola, 2014) amide. scaling, and infiltration . Group II: vehicle cream. using four-point scale was observed in group I.

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Novel Herbal-based Cream. 32 Twice daily for 42 days. A reduction in Investigator No adverse side effects were (Barak-Shinar, Del Río, & Static Global Assessment, noted. Green, 2017) desquamation (scaling), induration (inflammation), and erythema (redness) as well as self-assessed pruritus parameters. Oral Homeopathic Solution. 41 Every morning for 10 The disease state of the Mild stomach upset, stom- (Smith, Baker, & Williams, weeks. active group was improved ach pain, and nausea. 2002) . Active group: homeo- significantly compared to pathic solution. placebo group. . Placebo group: vehicle drink. Pimecrolimus 1% cream. 21 Twice daily for 14 days. Significant improvement Mild burning. (de Moraes et al., 2007) from baseline in terms of erythema, scaling, and infiltration/population. Pimecrolimus 1% cream. 40 Twice daily for 2 weeks. Group I and II have the Mild burning. (Firooz et al., 2006) Followed up every 2 weeks same efficacy with no signif- for 4 weeks. icant differences in patients’ . Group I: 1% pimecro- baseline data, response to limus. treatment, and relapse rate. . Group II: 1% hydrocortisone acetate. Pimecrolimus 1% cream. 60 Twice daily for 4 weeks. Higher level of satisfaction No adverse side effects were (M. Goldust, Rezaee, & Ra- . Group I: 1% pimecro- was observed group II. noted. ghifar, 2013) limus. . Group II: 2% sertaconazole. Pimecrolimus 1% cream. 5 Twice daily for 16 weeks. All participants noted a No adverse side effects were (High & Pandya, 2006) marked decrease in the noted. severity. Pimecrolimus 1% cream. 20 Twice daily for 4 weeks. Improvements were noted No adverse side effects were (B. S. Kim et al., 2007) in the global assessment of noted. disease severity. Relapse was observed after discontin- uation. Pimecrolimus 1% cream. 48 Twice daily for 6 weeks. In both groups, effective Mild burning, pruritus, (Koc, Arca, Kose, & Akar, . Group I: 1% pimecro- results in clinical severity irritation, and erythema. 2009) limus. scores. . Group II: 2% ketoconazole. Pimecrolimus 1% cream. 16 Twice daily for 2 weeks. Statistically significant Temporary pruritus. (Ozden, Tekin, Lter, & An- reductions in the scores of karali, 2010) all parameters (clinically, 4-point score, Visual Ana- logue Scale). Pimecrolimus 1% cream. 19 Twice daily for 7 days. Subjects’ average assessment Mild burning and irritation. (Rallis, Nasiopoulou, Kousk- Additional period of 7 days, score was high (9.73). oukis, & Koumantaki, 2004) if needed, until complete clearance was achieved. In cases of recurrence a 5-day course was additionally applied. Pimecrolimus 1% cream. 22 Twice daily until absence of In group I, a reduction Mild burning sensation in (Rigopoulos, Ioannides, symptoms. in erythema, scaling and group I. Kalogeromitros, Gregoriou, & . Group I: 1% pimecro- pruritus, although slightly Katsambas, 2004) limus. slower than betamethasone, . Group II: 0.1% beta- but it is not statistically methasone 17-valerate. significant.

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Pimecrolimus 1% cream. 52 Twice daily until lesions A reduction in pruritus, Pruritus, burning, erythe- (Tatlican, Eren, & Eskioglu, completely disappeared. erythema, and scaling. The ma. 2009) mean cure and mean remission times were 13.34 and 47.98 days, respectively. Pimecrolimus 1% cream. 96 Twice daily for 4 weeks. The superiority of pimecro- No adverse side effects were (Warshaw et al., 2007) . Group I: 1% pimecrolimus was observed noted. limus. . Group II: placebo. Pimecrolimus 1% cream. 30 . Group I: cream twice In all groups, a significant Erythema, localized burn- (Zhao et al., 2018) daily for 2 weeks, mois- decrease in clinical severity ing sensation, aggravated turizer twice daily for scores. The improvement of pruritus. 2 weeks. total severity score in Group . Group II: cream twice III was more remarkable daily for 2 weeks, then than groups I and II. once daily for 2 weeks. . Group III: cream twice daily for 4 weeks. Quassia amara 60 Twice daily for 4 weeks. In all groups, a decrease in No adverse side effects were (Borda et al., 2019) . Group I: 4% Quassia SD mean severity score. In noted. amara group I, statistically signif- . Group II: 2% keto- icant difference in avoiding conazole SD relapse. . Group III: 1% ci- clopirox olamine Solution of urea, lactic acid, 299 . Study I: once daily ap- In both studies, 4-weeks Mild burning. and propylene glycol. plication for 4 weeks of desquamation scores were (Emtestam, Svensson, & K301 (K301a or K301b) significantly improved for Rensfeldt, 2012) or placebo, followed by K301 compared to placebo. maintenance treatment 3 times weekly for 4 weeks . Study II: once daily ap- plication for 4 weeks of K301 (a) or placebo. Tacrolimus 0.1% ointment. 16 Every night until absence of Improvement in all the Mild-to-moderate applica- (Braza, Dicarlo, Soon, & clinical symptoms, and then mean lesional erythema tion site pruritus ⁄ burning, Mccall, 2003) for 7 days thereafter. scores, mean scaling, mean mild sunburn. investigator global assessment, and mean subject global assessment scores. Tacrolimus 0.03% cream. 60 Twice daily for 4 weeks. In both groups, significant No adverse side effects were (Mohamad Goldust, Rezaee, . Group I: 2% sertacon- reductions in SI score, signs, noted. Raghifar, & Hemayat, 2013) azole. and symptoms. In group I, . Group II: 0.03% tacro- a higher level of satisfaction limus. was observed.

Tacrolimus 0.1% cream. 75 Treatment for 10 weeks. In group I and II, significant Burning and tingling sen- (T. W. Kim et al., 2013) . Group I: cream, twice improvement in erythema, sation. weekly. scaling and pruritus. The . Group II: cream, once mean recurrence rate ac- weekly. cording to global assessment . Group III: placebo was significantly higher twice weekly. in group II compared to group I. Tacrolimus 0.1% cream. 18 Treatment daily for 28 days A complete clearance of SD Mild local burning and (Meshkinpour, Sun, & Wein- or until complete absence of with a grade of 0 for ery- irritation. stein, 2003) symptoms. thema, scaling, and global severity.

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Tacrolimus 0.1% cream. 30 Twice daily for 12 weeks. Tacrolimus 0.1% cream Flushing and irritation in (Papp, Papp, Dahmer, & . Group I: 0.1% tacro- was equally effective as group I. Clark, 2012) limus. hydrocortisone 1% cream . Group II: 1% hydrocor- but required significantly tisone. fewer treatment applications to achieve the same level of disease control. Tea tree oil 5% gel. 54 Three times daily for 4 In group I, a reduction in No adverse side effects were (Roy et al., 2014) weeks. erythema, scaling, itching noted. . Group I: 5% tea tree and greasy crusts oil gel. . Group II: placebo gel. Tea tree oil 5% shampoo. 126 Daily for 4 weeks. In group I, an improvement No adverse side effects were (Satchell, Saurajen, Bell, & . Group I: 5% tea tree oil in whole scalp lesion score, noted. Barnetson, 2002) shampoo. total area of involvement . Group II: placebo. score, the total severity score, the itchiness, and greasiness. Vitreoscilla filiformis biomass. 60 Once daily for 4 weeks. In group I, a high improve- No adverse side effects were (Guniche et al., 2008) . Group I: 5% LRP-bio- ment of total clinical score noted. mass lotion (sum of erythema and . Group II: vehicle lotion. scaling subscores) and level of pruritus. Zinc pyrithione 1% shampoo. 343 Twice weekly for 4 weeks. In both groups, flakiness Mild pruritus and erythema (Piérard-Franchimont, Goffin, . Group I: 2% keto- improved significantly. In in both groups. Decroix, & Piérard, 2002) conazole. group I, the overall clearing . Group II: 1% zinc was statistically greater pyrithione. and there was less clinical relapse. Zinc pyrithione (potentiated) 620 Three times weekly for 4 In group I, better adherent No adverse side effects were shampoo. weeks. scalp flaking severity (ASFS) noted. (Schwartz, Mizoguchi, & . Group 1: potentiated and overall scalp health. Bacon, 2013) zinc pyrithione shampoo . Group II: zinc pyrithione/ climbazole combination

Herbal and Zinc Pyrithione-based Therapy of Isotretinoin oral Shampoo and Scalp Lotion In these studies, oral isotretinoin was found effec- This therapy is a patented Kamedis Derma-Scalp tive due to its ability to suppress secretion of sebaceous Dandruff Therapy shampoo and scalp lotion (Kame- glands by reducing their size, decreasing proliferation, dis Ltd., Tel-Aviv, Israel). The main ingredients are and inducing basal sebocyte apoptosis. It has anti-in- zinc pyrithione and botanical extracts of Phelloden- flammatory properties, including decreasing interleu- dron amurense bark, Portulaca oleracea, Sapindus mu- kin production by keratinocytes and sebocytes, poly- korossi fruit, Indigofera tinctoria, and Rheum palma- morphonuclear cell migration, and Toll-like receptor tum root. Rheum palmatum reduces sebum secretion. 2 activity (de Souza Leão Kamamoto et al., 2017). In Zinc pyrithione and botanical ingredients especially its higher dose (0.5-1.0mg/kg/day), oral isotretinoin in the scalp lotion offer potential anti-inflammatory, has been controversially reported to trigger flaring, antimicrobial, and antifungal properties (Barak-Shi- depression, suicidal ideation, and inflammatory bow- nar et al., 2017). el disease, and pseudotumor cerebri. It is still debated whether those adverse reactions are definitely caused Honey (Crude Honey) by isotretinoin, and if they are, such reactions are rare In the study, honey was found to be beneficial due (Geißler et al., 2003; Leyden, Del Rosso, & Baum, to its antibacterial, antifungal, and antioxidant prop- 2014). erties (Al-Waili, 2001).

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Lipohydroxy acid containing shampoo Nicotinamide Lipohydroxy acid (LHA) was found useful in man- Nicotinamide (NCT) shows effective result against aging SD due to its ability to induce exfoliation and SD because of its cellular inflammation regulation as stimulate epidermal renewal. It also has antimicrobi- well as its ability to regulate stratum corneum inter- al and anti-inflammatory properties. In vitro exper- cellular lipid synthesis. It blocks pro-inflammatory iments showed that LHA has similar antimicrobial cytokines and poly(ADP-ribose) polymerase (PARP), properties to octopirox (piroctone olamine) against which influences inflammatory processes through Malassezia ovalis (Seite et al., 2009). modulating different transcription factors. In stratum corneum, it increases ceramide and other intercellular Lithium lipids, maintaining the epidermal permeability barrier Lithium was more superior in controlling SD (Fabbrocini et al., 2014). compared to ketoconazole 2% or placebo. The exact Novel herbal based handcream mechanism of action of lithium salts in SD remains unclear. It could act by inhibiting Malasezzia furfur This handcream is a patented Seborrheame- which colonizes the cutaneous lesions. In also has an dis Face Cream (Kamedis, Israel), which is a barri- anti-inflammatory activity by inhibiting the produc- er-based, non-steroidal cream infused with herbal tion of arachidonic acid, which is the first step induc- extracts to manage the clinical manifestations and ing the production of leukotriene and prostaglandin symptoms of facial SD, such as erythema, scaling, and (Dreno et al., 2003; Dreno & Moyse, 2002) pruritus. The cream used in this study forms a dense layer over the affected areas and prevents oxygen sup- Metronidazole ply, which resulted in anaerobic environment that in- Metronidazole is an antibiotic with efficacy against hibits pathogen growth. Its herbal ingredients namely anaerobic bacteria. It acts through DNA destruction dipotassium glycyrrhizate (also known as licorice), and prevention of nucleic acid synthesis, in the anaer- offers potential anti-inflammatory, antimicrobial, and obic organisms and cells. It also has anti-inflammato- antifungal, properties (Barak-Shinar et al., 2017). ry effect through inhibition of leukocyte chemotaxis Oral Homeopathic Solution Consisting of Po- and prevention of inflammatory mediators release tassium Bromide, Sodium Bromide, Nickel Sulfate, from neutrophils, decreasing oxidative tissue damage. and Sodium Chloride The exact mechanism of action of metronidazole in SD is not yet clear, it might be acting through these This study was based on information about how anti-inflammatory properties (Siadat et al., 2006). inorganic bromide was found to be effective to treat chronic skin conditions such as psoriasis, with has a Myrtus communis L. solution similarity with SD in terms of its primary biochemical Myrtus communis L. is a shrub that grows from the defect. Although the mechanism of action for nickel Mediterranean region to the northwestern Himala- and bromide therapy is not fully understood, a theory yas. It has different components, such as polyphenols, is proposed whereby a genetic error of nickel-depen- myrtucommulone (MC), semi myrtucommulone (S- dent metabolism exists. Bromide has also been found MC), 1 and 8-cineole, alpha-pinene, myrtenyl acetate, as an effective antipruritic agent (Smith et al., 2002). limonene, linalool and alpha-terpinolene. Those com- Pimecrolimus 1% cream ponents contribute to myrtus solution having its anti-bacterial, anti-fungal and anti-inflammatory effect Pimecrolimus cream 1% is a new topical macro- (Chaijan et al., 2018) lactam immunomodulator that inhibits T-cell activation and proinflammatory cytokine production (B. S. Narrow-band ultraviolet B (TL-01) phototherapy Kim et al., 2007), which is to prevent T-cell activation This study showed favourable results, although the by down-regulating T-cell production of T-helper mode of action of narrow-band UVB in SD was still cells type 1 and type 2. Pimecrolimus also prevents not fully understood. It may be related to its modula- the IgE/ antigen-mediated degranulation of mast cells tory effect on inflammatory and immunological pro- (Warshaw et al., 2007) cesses in the skin. There was also a report of a direct Quassia amara effect of UV irradiation on P. ovale leading to ultra- structural changes and growth inhibition (Pirkham- Quassia amara is a shrub from South America. It mer et al., 2000). was effective for SD because of its high levels of active phytochemicals, including the triterpenoid quassi-

84 FABAD J. Pharm. Sci., 45, 1, 77-89, 2020 noids. It has anti-inflammatory properties, as well as evidence-based recommendations for various alter- antimicrobial and antifungal activities especially on native modalities. People often choose alternative Malassezia spp. Yeast (Borda et al., 2019). modalities because of a perceived lower risk of side effects, and or dissatisfaction with traditional treat- Solution of urea, lactic acid, and propylene gly- ments (Farahnik, Sharma, Alban, & Sivamani, 2017). col (K301) Since the suggested underlying pathogenic mecha- This study showed positive results. Propylene gly- nisms of SD are fungal proliferation and inflammation, col, lactic acid, and urea have all been shown to in- the conventional treatments used are topical antifun- hibit growth of bacteria and or fungi. Therefore when gal and anti-inflammatory agents such as corticoste- combined, the ingredients of K301 provide a solution roid (Borda et al., 2019). Topical antifungals have been with keratolytic, exfoliating, anti-fungal and hydrat- used with varying success (Collins & Hivnor, 2012). ing properties (Emtestam et al., 2012). In a study comparing antifungal agent ketoconazole Tacrolimus 0.1% ointment and placebo, the results showed that the people treat- Tacrolimus 0.1% ointment showed great results ed with the topical antifungal agent achieved complete against SD. It inhibits calcineurin, a calcium-depen- resolution of SD symptoms compared to those in the dent phosphatase essential for T-cell activation and placebo group, but the results were statistically het- proinflammatory cytokine production (Braza et al., erogeneous and could not be explained by subgroup 2003). analyses of dose, mode of delivery nor conflict of interest. Topical ketoconazole showed similar efficacy Tea tree oil when compared to corticosteroids, but corticosteroids Tea tree oil (TTO) or Melaleuca alternifolia shows showed a two-fold greater risk of side effects (Okokon, effective results in reducing SD symptoms. Although Verbeek, Ruotsalainen, Ojo, & Bakhoya, 2015). Corti- the exact mechanisms of TTO gel in treatment of SD costeroids are effective in the short-term management is unknown. It may be associated with its antifungal of SD, but they have limited long-term use because properties, which may be due to its terpenoids con- of the potential for hypothalamic-pituitary-adrenal tent. It also has anti-inflammatory property (Roy et (HPA) axis suppression. In a case study of patients al., 2014; Satchell et al., 2002). applying high-potency topical corticosteroids for up to one year, results showed low cortisol levels and Vitreoscilla filiformis biomass clinical signs of Cushing syndrome as a result of HPA Vitreoscilla filiformis is a Gram-negative bacteria axis suppression (Gilbertson, Spellman, Piacquadio, found in thermal spa water classically used for der- & Mulford, 1998). In a clinical study where the ma- matological treatment. In this test, the microorgan- jority of the patients applied topical corticosteroid ism biomass was cultured in a medium prepared with for one week to one month with a regimen of twice La Roche Posay (LRP) spa water. LRP-biomass was or more per day, skin adverse effects emerged, such shown effective in improving SD symptoms, probably as: tinea incognito (49.46%), acne (30.27%), cutane- due to its tolerogenic effect and its ability to modulate ous atrophy (12.97%), rosacea (11.08%), topical ste- the defensins synthesis that may decrease scalp micro- roid-dependent facies (9.73%), telangiectasia (8.38%), flora dysregulation (Guniche et al., 2008). hypopigmentation (7.57%), irritant contact dermatitis (5.68%), striae (4.59%), pyoderma (4.32%), perioral Zinc pyrithione dermatitis (2.70%), and hypertrichosis (1.35%) (Fu- As mentioned above, zinc pyrithione has anti-in- rue et al., 2003; Meena et al., 2017)546 children, and flammatory, antimicrobial, and antifungal properties. 515 adolescents and adults. Zinc pyrithione is known to have an efficacy against Herbal therapies for SD reviewed in this study in- M.furfur (Barak-Shinar & Green, 2018). There is also clude herbal shampoo and scalp lotion, honey, Myr- a potentiated zinc pyrithione shampoo that shows tus communis L. solution, herbal handcream, Quas- better synergistic effect than normal zinc pyrthione sia amara, tea tree oil, and Vitreoscilla filiformis.For shampoo during an in-vitro microbiology demonstra- thousands of years, herbal therapies have been used tion (Schwartz et al., 2013). with great results in treating dermatologic disorders DISCUSSION in Europe and Asia. However, in the United States and many other countries herbal products are still con- Nowadays, more people rely on non-conventional, sidered as dietary supplements, which means there is alternative modalities to meet their healthcare needs. still no standardisation of active ingredients, purity, or It is important that physicians remain informed on concentrations (Bedi & Shenefelt, 2002). Therefore, 85 Djunaidi even though the herbal studies showed favourable reviewed were sponsored by patented brands, which results in treating SD, learning about and using these may increase the risk of outcome bias. Additionally, non-conventional treatments remain challenging. some of the studies included had small sample size or did not have a control group, making it difficult to In this review, the most highly studied non-herbal draw specific conclusions about a particular therapy alternative therapy for SD was calcineurin inhibitors used. (pimecrolimus with twelve studies and tacrolimus with five studies), where all showed positive clini- CONCLUSION cal improvements. Even so, treatment periods var- Seborrheic dermatitis remains a challenging dis- ied largely between existing studies, ranging from 2 ease that may cause significant morbidity. With its to 16 weeks. For pimecrolimus 1% cream, in a study still uncertain pathophysiology and etiology, there comparing different courses to explore an optimal is a huge room for innovative therapies to emerge. regimen, results showed that the regimen of 4-week While traditional therapies may offer immediate relief twice-daily course may provide longer remission for many patients, risks of adverse effects may lead to time and less frequent relapse (Zhao et al., 2018). As explorations of complementary and alternative treat- for tacrolimus 0.1% cream, there was a study where ments. While clinical evidence and quality for these SD began to recur within 2 weeks after therapy was treatments are relatively less than that of more con- completed (Meshkinpour et al., 2003). A twice-weekly ventional therapy, well-designed trials do exist with treatment with 0.1% tacrolimus ointment for facial SD occasional agreements between studies. Undeniably, seems to provide longer remission time (T. W. Kim et more rigorous randomized controlled trials are need- al., 2013). ed to more accurately determine the safety and effica- The most common side effects observed in cal- cy of these therapies. For now, it is imperative to know cineurin inhibitor studies were mild burning sensa- which alternative therapies exist and what potential tions, erythema, and pruritus. However, the adverse side effects that may occur so better patient counsel- effect profile of calcineurin inhibitors in terms of cel- ing could be performed. lular activity and pharmacologic profile were still a lot CONFLICT OF INTEREST safer than that of corticosteroids, making it more favourable for long term use. This is because the T-cell The authors declare no conflict of interest, finan selectivity of pimecrolimus and tacrolimus contrasts cial or otherwise. with the multiple targets of corticosteroids, includ- REFERENCES ing inflammatory cells, fibroblasts, and keratinocytes. 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